Fetal hemoglobin induction by the histone deacetylase inhibitor, scriptaid

J. Johnson, R. Hunter, R. McElveen, X. H. Qian, B. S. Baliga, B. S. Pace

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Many different classes of drugs induce fetal hemoglobin (HbF) including histone deacetylase (HDAC) inhibitors such as butyrate and trichostatin A. Although these agents induce gamma-globin expression in culture many are ineffective in vivo, therefore research efforts continue to identify clinically useful fetal globin inducers. We and others demonstrated a role for p38 mitogen activated protein kinase (MAPK) in gamma-globin promoter activation by HDAC inhibitors. In this study we determined the ability of scriptaid, a novel HDAC inhibitor, to induce gamma-globin expression via p38 MAPK signaling. Scriptaid induced gamma-globin in K562 cells and human erythroid progenitors. Furthermore the p38-selective inhibitor SB203580 completely reversed the ability of scriptaid to induce HbF. To test the potential efficacy of scriptaid in humans, in vivo studies were completed in beta-YAC transgenic mice where the gamma-gene is completely silenced. Scriptaid induced reticulocytosis and human gamma-globin mRNA synthesis. At a concentration of 1 mg/kg/day given by intraperitoneal injections twice weekly we observed a significant 1.8-fold increase in gamma-globin mRNA transcripts. The potential for scriptaid as a treatment option for sickle cell disease will be discussed.

Original languageEnglish (US)
Pages (from-to)229-238
Number of pages10
JournalCellular and Molecular Biology
Volume51
Issue number2
Publication statusPublished - Sep 5 2005
Externally publishedYes

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Keywords

  • Fetal hemoglobin
  • Gamma-globin
  • Histone deacetylase inhibitor
  • Scriptaid
  • p38 MAPK

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Johnson, J., Hunter, R., McElveen, R., Qian, X. H., Baliga, B. S., & Pace, B. S. (2005). Fetal hemoglobin induction by the histone deacetylase inhibitor, scriptaid. Cellular and Molecular Biology, 51(2), 229-238.